ABSTRACT Introduction Emery-Dreifuss Muscular Dystrophy (EDMD) is a disease characterized by skeletal muscle wasting, major tendon contractures, and cardiac conduction defects. Mutations in the gene encoding emerin cause EDMD1. Our previous studies suggested emerin activation of Histone Deacetylase 3 (HDAC3) to reduce Histone 4-Lysine 5 (H4K5) acetylation (ac) is important for myogenic differentiation. Methods Pharmacological inhibitors (Nu9056, L002) of histone acetyltransferases targeting acetylated H4K5 were used to test if increased acetylated H4K5 was responsible for the impaired differentiation seen in emerin deficient myogenic progenitors. Results Nu9056 and L002 rescued impaired differentiation in emerin deficiency. SRT1720, which inhibits the NAD + -dependent deacetylase Sirtuin 1 (SIRT1), failed to rescue myotube formation. Discussion We conclude emerin regulation of HDAC3 activity to affect H4K5 acetylation dynamics is important for myogenic differentiation. Targeting H4K5ac dynamics represents a new strategy for ameliorating the skeletal muscle wasting seen in EDMD1.